SCIE.03.1 - The role of SMN protein in translation: implications for Spinal Muscular Atrophy

Depletion of survival motor neuron (SMN) protein, caused by homozygous deletion or mutations in the SMN1 gene, causes SMN protein loss and Spinal Muscular Atrophy. SMA is the most common genetic cause of infant mortality, with an incidence of 1 in 6000 live births. Left untreated, SMA is associated with a loss of lower motor neurons, leading to muscle atrophy and eventually to paralysis and death. Despite very encouraging developments, it is clear that SMN-targeted therapies are not sufficient to "cure" SMA patients. Thus, further studies of SMN biology are required to better understand the condition and develop more effective therapeutic options. In our Telethon project, we leveraged our cutting edge experimental and computational approaches to study ribosome positioning along mRNAs at single nucleotide resolution and showed robust translational defects occurring in multiple tissues of three mouse models of disease. Using in vivo, in vitro and in cellulo models of disease coupled to positional analysis of ribosomes at single nucleotide resolution, proteomics and structural analysis, we revealed at unprecedented detail the functional aspects of SMN/ribosome interactions and identified pre-symptomatic defects in multiple tissues and mouse models of SMA that impact a plethora of biological processes. Our results not only expand our understanding of SMN biology and SMA disease pathogenesis but bring us in the unique position to move from fundamental and biology-based hypotheses to the development of second-generation therapies.